The study was conducted at two sites: the HIV clinic of VA Connecticut Health Care System in West Haven and the University of Connecticut Infectious Disease Study Center, which is located in the City of Hartford Health Department in Hartford, Conn. The study was approved by institutional review boards at both of the participating sites.
Patients at these two sites were invited to participate if they were currently being treated with any antiretroviral medication. Antiretroviral regimens were not altered for study participation, but enrollment was deferred if the subject's provider anticipated a change in regimen during the next 12 weeks. Once enrolled in the study, however, treatment changes for clinical reasons were allowed at the discretion of the primary provider and did not require removal from the study.
Subjects who scored 23 or less on the Folstein Mini Mental Status Exam, relied on others to administer medications, or could not accommodate the use of MEMS devices in their daily routine were excluded. After giving informed consent, eligible subjects were administered a modification of a 5-item neuropsychological test battery used previously,8
the Functional Assessment of HIV Infection Quality of Life (FAHI),9
the Symptom Checklist 90 (SCL-90),10
an 11-item measure of medication side effects, the Addiction Severity Index Version 5,11
the Multidimensional Health Locus of Control Scale,12
and the Beck Depression Inventory.13
A urine toxicology screen (for opiates, cocaine, cannabis, and amphetamines) was also obtained.
Subjects were asked to generate a personalized time-of-day schedule for taking each prescribed antiretroviral medication. Study personnel reviewed the schedule to make sure that it was consistent with prescription instructions for each medication. This schedule became the basis for determination of individual adherence. If a subject taking a thrice-daily medication normally opened a bottle twice daily and removed a third dose at one of those times, the schedule reflected only the two scheduled bottle openings, thus allowing patients to continue their usual routines. Subsequently, all antiretroviral medications were dispensed in bottles with MEMS caps. Subjects took medications without any other intervention for a 1-week baseline period.
After the 1-week baseline period, MEMS cap data were downloaded. The percentage of correct doses, defined as the number of bottle openings within 2 hours before or after the agreed upon time, was calculated for each antiretroviral drug. The drug with the lowest baseline adherence was the focus of subsequent training and was designated as “primary.” Urn randomization14
was employed to ensure comparable baseline adherence to the primary medication in each study group. Subjects were randomized to 1 of 3 interventions to begin at the randomization visit (week 0) and at 4 weekly visits (weeks 1 to 4). Data were collected at visits 8 and 12 weeks after randomization (follow-up period). To minimize differential attrition among the groups, all subjects were compensated for attending each study visit (a maximum of $280 if all study visits were kept). Two research assistants without medical training and having no affiliation with the HIV clinic conducted all of the screening, baseline assessments, and training sessions.
The interventions were based upon Cramer's method of cue-dose training which involves linking medication-taking to individualized daily habits (e.g., meals, tooth brushing) which then serve as cues for taking medication.7
A trainer works with individual patients to develop a schedule for taking medication and reminders for dose times (“cues”) that were customized to the patient's lifestyle. The MEMS device records bottle-opening dates and times through a microprocessor in the medication bottle cap. This record is the basis for corrective feedback at meetings with a trainer. We employed this method with and without an additional contingency reinforcement of graduated cash payments based on consecutive correctly timed bottle openings. The specific intervention arms, which are summarized below, were described in detail in a study manual which was used by trainers to minimize variation in the interventions among subjects or between trainers.
Control training (C): Subjects were asked about medication adherence during the week preceding each visit and were encouraged in their efforts to improve adherence. No MEMS calendar was generated for feedback, but MEMS data were collected for measurement of adherence.
Cue-dose training (CD): Subjects were asked to identify cues which would help them remember to take their medications correctly. Subjects were shown a MEMS-generated calendar of their taking of the primary medication during the previous week. If MEMS data revealed missed doses, the counselor would query the subject about the cue for that dose. If there was a consistent pattern of missed doses, the trainer would suggest alternative cues. Subjects were encouraged to take other medications at the cue for the primary medication if possible or to develop alternate cues.
Cue-dose training plus cash reinforcement (CD+CR): Subjects received cue-dose training as above. At weekly meetings, they were also given cash reinforcement for each dose of the primary medication taken within 2 hours of the agreed-upon time. The reinforcement began at $2 per correct dose and increased with each consecutive correct dose to a maximum of $10 per day. If a dose was not taken within 2 hours of the agreed-upon time, the reinforcement was reset to $2. Thus, a subject in this group who took 100% of doses within 2 hours of the agreed-upon time over 4 weeks would receive approximately $280 in addition to the reimbursement for study visits that all subjects received.
Viral load data were collected at baseline (or within 4 weeks prior to study entry) and at the week 12 study visit. HIV RNA values were measured using the Amplicor RNA-PCR Assay (Roche; Alameda, Calif) with lower limit of quantifiable values of 400 copies/mL. Samples that produced a signal below this were assigned an intermediate value of 200 copies (2.3 log 10), and samples that produced no detectable signal were assigned a value of 0.5 log 10 copies/mL.
Zidovudine concentrations were measured in a subset of subjects by radioimmunoassay using the ZDV-Trac kit (DiaSorin, Inc., Stillwater, Minn) as previously described in a study of methadone effects on zidovudine pharmacokinetics.15
Using the time-concentration data from the control group of that study, 98% confidence intervals were constructed for zidovudine concentrations at each time point. Concentration intervals for later time points were determined by log-linear extrapolation from the upper and lower bounds. Measured zidovudine concentrations falling within the 98% confidence limits for the time since last MEMS-recorded opening were interpreted as confirming medication ingestion at the time of the bottle opening.
Adherence (percentage of prescribed doses taken on time) as measured by MEMS was calculated separately for the primary and mean of all nonprimary antiretroviral medications for each subject at weekly intervals. In order to examine the change in adherence over time for subjects in each group, we used random effects regression modeling. Random effects regression, a method similar to repeated measures analysis of variance, was used to model group and time effects because it allows use of all available data, including data from subjects who did not complete the study.16,17
Four subjects stopped using the MEMS devices during the active intervention period (weeks 0 to 4) and 5 stopped during the follow-up period (weeks 5 to 12).
After exploratory analyses, planned comparisons of each of the active interventions to the control group were included in the model. Weeks 0 to 4 were analyzed to determine acute effects of the interventions. Weeks 4 to 12 were analyzed separately to determine if there were significant treatment effects after training had ended. At each week, mean adherence for each active treatment group was compared to the control group using Wilcoxon 2-sample test for nonnormally distributed data. Error terms (±) reflect standard errors of the mean. Baseline characteristics and change in viral load were compared using χ2and analysis-of-variance tests. Log units were used for viral load analysis.
For the analysis of correlates of baseline adherence, adherence was defined as the percentage of dosages of the primary antiretroviral taken within 2 hours of the prescribed time. Subjects whose adherence was less than the median (76%) were classified as noncompliant and those above were classified as compliant. Point biserial correlation and phi coefficients were calculated between independent variables and adherence.
Due to the exploratory nature of this study, the sample size was sufficient to detect only large treatment effects. A sample size of 18 subjects per group would have 80% power to detect an effect size of 0.7 at a significance of 0.05 based on power calculations for two-group contrasts. Due to the small sample size, no subgroup analyses were performed. As there were no significant differences in the pattern of outcomes between the subjects enrolled in West Haven and those enrolled in Hartford, all analyses include the combined subjects from both sites.